The heart function declines in the aged population. At age 80 years, LV contractile function is less than half of what it was at age 20 years. Aging, even in apparently healthy individuals without overt cardiovascular disease, is associated with damaged heart structure and comprised cardiac reserve function. Aging is a recognized risk factor for heart diseases. For instance, the prevalence of heart disease increases with age. Indeed, the mortality from heart diseases is higher in the aged than in the young population. Klotho is a recently-discovered anti- aging gene. Mutation of klotho gene expedites the aging process and shortens the life-span while over- expression of klotho slows the aging process and extends the life-span in mice. Klotho is predominately expressed in kidneys and secreted into the blood. In humans, the level of circulating klotho declines in the aged population. The objective of this application is to investigate, in animal models, if klotho deficiency causes hear damage and assess if in vivo expression of klotho or supplement of klotho protein prevents or attenuates aging-associated heart damage. The central hypothesis is that klotho gene deficiency impairs cardiomyocyte contractile function and upregulates collagen synthesis thereby impairing heart function and causing heart remodeling (fibrosis), respectively. The rationale for the proposed research is that if klotho deficiency causes heart damage, then, in vivo upregulation of klotho gene expression or supplement of klotho protein may be a novel approach for therapeutic intervention to prevent or attenuate aging-related heart damage and failure. This objective will be achieved by pursuing two coherent specific aims using a combination of several novel approaches. The two specific aims are: (1) Determine if klotho deficiency causes heart failure and remodeling and investigate the underlying molecular mechanisms. (2) Investigate if kidney-specific expression of klotho gene or supplement of klotho protein attenuates aging-associated heart damage. The proposed work is innovative and significant because it utilizes state-of-the-art approaches to address aging-associated heart damage which affects a large population but remains poorly explored. The results will reveal novel molecular pathways that mediate the pathogenesis of aging-related heart failure and remodeling. Completion of this project may provide new insights into therapeutic strategies for aging-related heart damage.